d-(alpha)-penicilloates



Patented May 9, 1950 UNITED PATENT OFFICE asgessc u- (a) ammchgpnrps skar LWintersteiner, New Brunswick, N. J., as; signo'r to E. R. Squibb & Sons,"-Netv York; N.'Y.,

a corporation of New York No Drawing. Application December 20, 19 5157,

' Serial No. usages 2 Glai ms. (Cl. 1260:3112) This invention relates general formula wherein X is a member of the class consisting of H, ammonium groups (including .hydrocarbom substituted ammonium groups) ,and hydrocarbon groups, and the penicilloic-acid residue is of the particular stereoisomeric form mainly resulting on alcoholysis (or mild alkaline hydrolysis) of penicillin G. 'Inis.stereo s9me is here designated by 11(0) directly preceding the term penicilloate, such designation'having been ac ceptedby the interested chemical researchigroups in this country. The invention .relates especially to compounds of .theaforementioned general formula wherein the various hydrocarbon groups are primary alkyl or primary aralkyl groups. The

synthesis of the compounds of this invention ,will

:provide potential intermediates for the synthesis, and precursors in .the vmold production, of

:penicillin and related chemotherapeutic agents.

The compounds of this invention wherein is H have been obtained by .alcoholysis.of.sodium penicillin G; andthe'resulting a-estershave-been converted into ammonium salts by treatmentwith ammoniaand amines,. as Well.asiurtherlesterified by treatment with diazomethanes.

The following examples are illustrative of the invention:

EXAMPLE 1 u-methyl-dw) mem'cilloate G 90 mg. crystalline sodium-penicillin G (cf. Wintersteiner et al. application Serial No. 540,140, filed June 13, 1944, now Patent No. 2,461,949, dated February 15, 1949) is dissolved in ml. absolute methanol. After standing hours at room temperature-during which time its [a]D falls from +304 to +157--most of the methanol is removed by vacuum distillation; water is added to the residue; the solution is acidified to pH 2 with phosphoric acid; and the acidified solution is extracted with several portions of ether. The (combined) ether extract is dried over NazSOr, and then filtered; most of I the solvent is removed by distillation; 50 ml. benzene is added to the residue; and distillation is continued in vacuo until the volume reaches about 20 ml. The reto compounds of the sulting solution is lyophilized, yielding the amethyl-dga) -penicilloate Gas a fluiiy white product melting at about 100 C." (with'gas evolution) and hat n MD of ;0 (in ,melheIlQ QSH .8 is in a reemen w th tha ca cu atqd i o .C HZ3Q 1NZ (0. 5,5105%; 610.5%

5 .65%; and 901th. ;8-. 7-%.

racemes s t or .a-memeaw r talia e 192 mg. a-methyl-dla) -penicilloate G is dissolvedin 5 ml. ethenthe solution is filtered, and (mfifi' mlf-benzylamine 0.5 ml. ether is added. The oil which precipitates iskept in the refrigerat'or'until it solidifies to a semicrystaliine mass; and "the product is collected by centrifuging, washed with ether, 'and recrystallized by dissolving in al'few drops 'thanol and adding ezgcess ethyl acetate. *The long needles thus obtained melt at 142 '3 C4 andthe OCH; content of the roduct (6.57%) agrees with that calculated for 5 of crystalline sod umrem um G le so ith ..ffi'if r;fimfin ge Winiersieine s @1- Patent i disso ved i bsolu m thanol A tstanding .41am;etfil qC-fidurie .WlliQl cue-me [aln drops to +145the solvent is removed by vacuum distillation, and the syrupy residue is dissolved in 5 ml. water. This solution is chilled, and 3.4 ml. of normal I-ICl solution is added; and the resulting precipitate is filtered off, Washed with water, and immediately dissolved in a few ml. ethanol by warming slightly. 40 The alcohol solution is chilled, Water is added dropwise until the solution becomes slightly turbid, and crystallization is induced by scratching. After standing for 12-16 hours at 4 C., the product is collected by filtration, and washed with water. The product, a-methyl-d(a)-penicilloate G, melts at 125-129 C. (yield 750 mg); and on recrystallization from aqueous methanol, hexagonal prisms melting at 133-134. C. and having an 113 of +105 (0.8% solution in methanol) are obtained. Additional material recovered from the mother liquor and recrystallized raises the yield to 812 mg. (56% of the theoretical).

The speed of methanolysis is affected by the presence of small amounts of basic substances acting as catalysis. Thus, complete methanolysis is effected at room temperature in a few hours by adding to the methanol freshly-prepared sodium ethoxide in amounts corresponding to 0.02-0.01 of a molar equivalent of the penicillin salt used, or of similarly small amounts of organic bases, such as piperidine.

EXAMPLE 4 Dimethyl (1(a) -pcnicilloate G 117 mg. a-methyl-dm) -penici1loate G is dissolved in 40 ml. ether, and an ethereal solution of diazomethane is added until a slight yellow color persists. After standing for 16 hours at 4 C., the solution is evaporated to dryness in vacuo, leaving the product as a fluffy white powder (yield 123 mg.). Its analysis (C; 56.40%; H,

6.14%; and OCHa, 15.60%) is in agreement with that calculated for C18H24O5N2S (C, 56.80%; H, 6.35%; and OCI-Ia, 16.32%).

EXAMPLE 5 Dimethyl (1(a) -pem'cz'lloate G An amount of a-methyl-d(a)-penicil1oate G obtainable from 2 g. crystalline sodium-penicillin G as described in Example 1 is dissolved in 50 ml.

ether, and the solution is treated with a slight excess of an ethereal solution of diazomethane. After standing a short time, the reaction mixture is distilled to remove the ether, and the residue is dissolved in a small volume of acetone. To this solution, 20 ml. dry ether is added, followed by hexane until a slight turbidity persists.

Crystallizationthen commences, and is furthered by the gradual addition of more hexane. After standing 24 hours at refrigerator temperature, the crystalline (but somewhat gummy) product is collected, washed with a mixture of ether and hexane, and dried (yield 1.33 two recrystallizations from a mixture of ether and hexane, the product melts at 8488 C., and i has an [(1113 of +855 (in methanol).

Following the procedure described in Example 1 (or 3) but substituting another alcohol for the methanol (e. g., absolute ethanol or benzyl alcohol), the corresponding a-ester is obtained. Following. the procedure described in Example 2 but substituting ammonia or some other amine (e. g., ethylamine or diethylamine) for the benzylamine, the corresponding ammonium salt of the a-methyl (or other hydrocarbon) ester is formed; and following the procedure described g.) After in Example 4 (0r 5) but substituting another esterifying agent for the diazomethane (e. g., phenyl-diazomethane) the corresponding derivative of the a-methyl (or other hydrocarbon) ester is formed.

The invention may be variously otherwise embodied within the scope of the appended claims.

I claim: 1. The compound of the formula om om-o-onooo-mm-omoui,

l mooomoun. wherein the penicilloic acid residue is of the particular stereoisomeric form mainly resulting on alcoholysis of penicillin G. r

2. The beta-benzyl amine salt of alpha-methyld-alpha benzylpenicilloate of the formula:

Nn-oH-oooH-mNomO OCHrO-NH-OH-G g s--- OH:

0 0 0 Ha Ha OSKAR WINTERSTEINER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Kushner Feb. 12, 1946 OTHER REFERENCES Number Dec. 20, 1943, p. 8

Abbott Report, A-16, Dec. 15, 1944, page 4; Upjohn Report U-16, Dec. 16, 1944, pp. 3 and "I, CPS No. 381.

Fleming. penicillin," (1946), page 29. 

2. THE BETA-BENZYL AMINE SALT OF ALPHA-METHYLD-ALPHA BENZYLPENICILLOATE OF THE FORMULA: 